A simple and effective co-catalyst for ring-closing enyne metathesis using Grubbs I type catalysts: A practical alternative to "Mori's conditions"

Article abstract of DOI:10.1002/chem.201001510

"Catch-and-release": Simple alk-1-enes are effective at liberating buta-1,3-dienes from vinyl alkylidene ruthenium complexes, as well as undergoing alkene-alkylidene exchange with enyne substrates to regenerate the alk-1-ene. This ability to "catch-andrelease" ruthenium alkylidenes allows alk-1-enes higher than ethylene ("Mori's conditions") to be used as a co-catalysts in terminal enyne metathesis with the Grubbs generation I complex (L=PCy3).

Full text of DOI:10.1002/chem.201001510

COMMUNICATION
DOI: 10.1002/chem.201001510
A Simple and Effective Co-Catalyst for Ring-Closing Enyne Metathesis
Using Grubbs I type Catalysts: A Practical Alternative to “Moriꢀs
Conditions”
Guy C. Lloyd-Jones,*[a] Alan J. Robinson,[a] Laurent Lefort,[b] and
Johannes G. de Vries[b]
In 1998 Mori reported[1] that ethylene improved turnover
in the ring-closing metathesis (RCM) of enynes (1!2),[2]
employing Grubbs generation I catalyst (3a); for example,
low yields of 2a–c under 1 atm argon, became near-quantita-
tive (99%) under 1 atm. ethylene.[1] Subsequent kinetic anal-
ysis[3] revealed that ethylene not only increases the turnover
frequency, but also reduces the impact of catalyst deactiva-
tion processes. The beneficial effect of ethylene is observed
with many enyne substrates, particularly those with terminal
alkyne moieties, and unsurprisingly, “Moriꢀs conditions”
have been widely adopted (Scheme 1).[4]
lysts, for example, 3a,[6] appear to favour the “ene-then-yne”
pathway (cycle A, Scheme 2).[7]
Scheme 2. The “ene-then-yne” cycle (A) for RCM of enynes 1!2 and
secondary cycle B to account for acceleration under “Moriꢀs conditions”
in which R=H.
For RCM involving phosphine catalysts, for example, 3a,
and terminal enynes, computational investigations[7,8] and
isotopic labelling experiments[3] support earlier proposals[5b,9]
that ethylene acts as an alkene surrogate for the enyne (1)
in the release of product (2) through alkene–alkylidene ex-
change with intermediate 5.[10] A second alkene–alkylidene
exchange of 6 (R=H) with 1, to generate 4, connects the
secondary cycle B with primary cycle A,[11] liberating the
ethylene (R=H), which thus acts as a co-catalyst.
Scheme 1. RCM of enynes 1a–c under an ethylene atmosphere (“Moriꢀs
conditions”).
Two basic mechanisms have been proposed for the RCM
of enynes involving intermolecular[5] metal–alkylidene prop-
agation. These mechanisms are often referred to as the
“yne-then-ene” and “ene-then-yne” pathways.[2] Evidence
for both pathways has been presented, and phosphine cata-
During our earlier study of “Moriꢀs conditions”[3] we
noted that co-reaction of the about threefold-faster-reacting
substrate 1c with 1a resulted in a small but noticeable de-
crease in the rate of RCM of 1a. This suggested to us that
an appropriately “tuned” alk-1-ene might be able to act as
an efficient co-catalyst, in a manner analogous to ethylene.
Herein we report on a kinetic and isotopic labelling investi-
gation into this concept, and the development of a simple
alkene co-catalyst that provides practical advantage to
“Moriꢀs conditions” for the RCM of terminal enynes using
Grubbs I catalyst (3a).
[a] Prof. Dr. G. C. Lloyd-Jones, Dr. A. J. Robinson
School of Chemistry, University of Bristol
Cantockꢀs Close, Bristol, BS8 1TS (UK)
Fax : (+44)117-925-1295
E-mail: Guy.Lloyd-Jones@bris.ac.uk
[b] Dr. L. Lefort, Prof. Dr. J. G. de Vries
DSM Innovative Synthesis BV, A unit of DSM Pharma
PO Box 18, 6160 MD Geleen (the Netherlands)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001510.
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9449

On consideration of the reaction of higher alkenes (R¼
H) with intermediate 5, at which cycle B partitions from
cycle A, it immediately becomes apparent that the regiose-
lectivity of the alkene–alkylidene exchange, which is degen-
erate when R=H, will have a crucial impact on the out-
come: orientation “a” (Scheme 3) will result in acceleration
Scheme 3. The impact of regioselectivity on the alkene-alkylidene ex-
change of an added alkene (RCH=CH2) with vinylalkylidene intermedi-
ate 5a.
Figure 1. a) Pseudo first-order rate constants (kOBS
(0.06m) catalysed by 3a in the presence of n-dec-1-ene (10-500 mol%),
with analysis of partitioning by cycles A (0.38) and B (0.62) at 0.06m dec-
) for RCM of 1a
1-ene. b) Mole fraction CD2 at exo-alkene terminus (x D ) in product
2
[2H2]-2a and reference product [2H9]-2a as a function of time for reaction
shown in Scheme 4. Approximately 38% conversion of 1a is achieved at
30 min. The curve through the data points for [2H9]-2a is based on first-
order equilibrium kinetics, where t0.5 =3 min and K=0.66.
of 1!2; whilst orientation “b” will result in ring-closing-
cross-metathesis (RC-CM) to generate 7.[12] Indeed, a wide
range of efficient Ru-catalysed RC-CM reactions of termi-
nal enynes with alkenes have been reported.[13] Of note,
however, is that a large excess (3–10 equiv) of the alkene is
employed, in conjunction with NHC-based catalysts;[7] the
outcome using phosphine-based[7] complex 3a has not been
reported.
To test our concept, we conducted RCM of enyne 1a
(0.06m in CH2Cl2) in the presence of 100 mol% of a series
of n-alk-1-enes (CxH2x) where x=5, 6, 8, 10, 12, 14, 18. The
consumption of 1a followed approximately pseudo first-
order kinetics (kOBS) and in each case a significant increase
in turnover rate was observed as compared to RCM in the
absence of alkene additive (k0).
cess, we included 20 mol% [2H7]-2a in the reaction
(Scheme 4), which underwent equilibration with the decene
(t0.5 ca. 3 min, see Figure 1b). This is about sevenfold faster
than RCM and the isotope ratio in the genuine products of
turnover (2a/ACTHNUTRGNEUNG
[2H2]-2a) were thus analysed by extrapolation
of a plot of mol fraction [2H2]-2a (xD ) versus time to t=0.
2
This gave an initial xD of 0.66, in reasonable agreement
2
with that predicted (0.62).[16]
A more detailed analysis of kOBS versus [CxH2x] for x=6,
10 and 14 indicated a first-order dependency on the alkene
concentration up to about 0.1m. Above this, there was
pseudo-zero-order dependency, indicative of saturation ki-
netics (kSAT, Figure 1a, x=10). Analysis of maximum rate ac-
celerations (kSAT/k0) versus x indicated that the longer al-
kenes (x=18!10) afford similar, approximately threefold,
acceleration. For the shorter alkenes, kSAT/k0 increased[14]
from about three- (x=10) to about sixfold (x=5); this trend
corresponds well with the 7.5-fold acceleration obtained for
1a[3] under ethylene (x=2; 0.12m) under “Moriꢀs condi-
tions”.[1,15]
To gain further evidence for co-catalysis by means of
cycle B, we employed [1,1-2H2]-decene to accelerate the
RCM of 1a. Analysis of kOBS versus k0 (Figure 1a) predicts
partitioning of 0.38 from cycle A and 0.62 from cycle B at
0.06m (100 mol%) decene. With the labelled decene, cycle
B will generate [2H2]-2a. However, the analysis is complicat-
ed by 1) the progressive dilution of the [1,1-2H2]-decene
with the unlabelled decene that is generated from cycle B
and 2) methylidene exchange between [1,1-2Hn]-decene and
[2Hn]-2a (n=0, 2). To estimate the impact of the latter pro-
Scheme 4. Dual-labelling test for decene co-catalysis[18,19] through cycle B,
see Figure 1.
In addition to their co-catalytic effect, the presence of n-
alk-1-enes also resulted in generation of the RC-CM prod-
ucts 7a (2–32%; R=Cxꢀ2H2xꢀ4); however, the n-alk-1-enes
did not undergo any detectable CM with 1a, indicating that
6!4 proceeds exclusively via orientation “b”. The propor-
tion of 7a generated relative to 2a increased with conver-
sion, with co-catalyst concentration, and approximately line-
arly with the size of R,[17] suggesting 7a arises through two
processes: 1) turnover of 1a by cycle B, but via orientation
“b”, Scheme 3; and 2) cross-metathesis (CM) of the alkene
with the product 2a. The CM process, degenerate in the ab-
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Ring-Closing Metathesis
COMMUNICATION
sence of an isotopic label, was also found to occur readily
with 2a and [13C2]-ethylene.[3]
ditive the reaction reached 42% conversion, and turnover
ceased after 60% conversion (12 h) due to catalyst deactiva-
tion.
Our preliminary experiments with simple n-alk-1-ene ad-
ditives suggested that a sterically unencumbered, but in
some way “activated”, terminal alkene could function as an
efficient co-catalyst at low concentrations, thus avoiding un-
desired RC-CM/CM to generate 7. Of note in this regard is
the observation that substrates 1bc, with electronegative
substituents at the allylic position turnover more efficiently
than 1a. This aspect is reinforced by the work of Imahori,[18]
who discovered that enyne substrates containing an allylic
hydoxyl group undergo RCM with such efficiency that
“Moriꢀs conditions” are not required. Kinetic studies[18b] sup-
ported an “ene-then-yne” mechanism in which the hydroxyl
group accelerates product release from vinylalkylidene inter-
mediate 5, a process exploited in a synthesis of isofagomi-
ne.[18a] We thus tested a range of simple allylic additives, in-
cluding allyl alcohol, allyl benzyl ether, allyl cyanide, allyl
dimethylmalonate, N-tosyl allylamine, allyl chloride and
allyl bromide, at 50 mol% loading with enyne 1a.
Rate accelerations were also found when 5 mol% allyl
bromide was added to the RCM of the more active sub-
strates 1bc. Although compared to 1a, rate accelerations
were less substantial, the effect of allyl bromide co-catalyst
was again to allow the RCM to go to completion, whereas
in its absence, turnover ceased at about 60% conversion. In-
terestingly, allyl alcohol emerged as a more powerful co-cat-
alyst than allyl bromide for 1c (but an inhibitor for 1a) sug-
gesting that a subtle “tailoring” of the additive to the sub-
strate might be required to balance reactivity (capture of 5)
versus stability (release of Ru back to the enyne from 6).
Despite many attempts, we were unable to prepare the
(=CHCH2Br)],[20]
bromoethylidene complex [RuCl2ACTHNUTRGENNUG(PCy3)2ACHTUGNTRENNGUN
which would provide an “all-in-one” catalyst/co-catalyst
system. We were however able to analyse the chloroethyli-
dene complex 3b (Scheme 5), which was more effective a
Whilst mild accelerations or decelerations were observed
with some combinations, allyl chloride and, in particular,
allyl bromide emerged as especially effective. Allyl bromide
afforded an approximate 20-fold rate enhancement, with no
trace of the RC-CM product 7a (R=CH2Br). However,
possibly due to extensive allylation of the phosphine ligands,
Ru-catalyst deactivation occurred after only about 75%
conversion of 1a.[19] Reducing the allyl bromide concentra-
tion lead to a substantial attenuation of the catalyst deacti-
vation process, without significant drop in acceleration;
indeed even with loadings as low as 2.5 mol%, sixfold rate
enhancement was observed. For substrate 1a, a loading of
5 mol% (3 mm) was found to be optimal, giving >98% con-
version in under 90 min, Figure 2. By comparison, 5 mol%
hexene gave 55% conversion, and in the absence of any ad-
Scheme 5. Pseudo bimolecular exchange rates (kEX dm3 molꢀ1 sꢀ1) and
equilibria (KEX, dimensionless) determined by 31P{1H} NMR for alkene
exchange with alkylidene complexes 3b–d (alkene
CH2Cl2 at 238C.
: [Ru]=1:1), in
catalyst than 3a, but only after an induction period. A
31P{1H} NMR study of alkene exchange rates indicated a
thermodynamic series 3b>3c>3d, but with no significant
difference in rates of displacement of allyl dimethyl malo-
nate from 3d by hex-1-ene (!3c) or allyl chloride (!3b).
It is important to note that these equilibria 1) include an en-
tropic component relating to both the “released” and the
“captured” alkene; and 2) relate to the “off-cycle” diphos-
phine complexes (3), rather than the catalytically active
monophosphine species (e.g., 5 or 6) in which there may be
the possibility for other interactions at the site vacated by
Cy3P.
In summary, we have demonstrated the ability of simple
alkenes to act as efficient co-catalysts for RCM reactions of
terminal enynes, catalysed by the commercially available
Grubbs generation I catalyst 3a. Preliminary mechanistic in-
vestigations with [1,1-2H2]-decene support an ene-then-yne
type cycle, with the alkene acting to facilitate product re-
lease from vinylalkylidene intermediate 5.[10] From a range
of allylic substituents in the alkene co-catalyst (n-alkyl, OH,
Figure 2. RCM of 1a (0.06m) to 2a catalysed by 5 mol% 3a, in the pres-
ence and absence of hex-1-ene or allyl bromide as co-catalyst. Solid lines
through data are based on first order decay of 1a with the half-life indi-
cated; the dashed lines schematically indicate progressive deviation from
this due to catalyst deactivation. The reaction without additive failed to
reach completion (60%, 12 h).
OBn, TsNH, CN, CHACHTUNRGTNEUNG(CO2Me)2, Cl and Br) allyl bromide
emerged as particularly effective. At loadings as low as
5 mol% it offers>15-fold rate accelerations, and greater
Chem. Eur. J. 2010, 16, 9449 – 9452
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G. C. Lloyd-Jones et al.
[6] E. L. Dias, S. T. Nguyen, R. H. Grubbs, J. Am. Chem. Soc. 1997, 119,
3887–3897.
[7] H. Clavier, A. Correa, E. C. Escudero-Adꢄn, J. Benet-Buchholz, L.
Cavallo, S. P. Nolan, Chem. Eur. J. 2009, 15, 10244–10254.
[8] J. J. Lippstreu, B. F. Straub, J. Am. Chem. Soc. 2005, 127, 7444–7457.
[9] a) A. J. Giessert, N. J. Brazis, S. T. Diver, Org. Lett. 2003, 5, 3819–
3822; b) C. S. Poulsen, R. Madsen, Synthesis 2003, 1–18.
numbers of catalyst turnovers, with no competing RC-CM
(!7). Being cheap, easily handled and effective at low con-
centration (3 mm) it offers a practical alternative to “Moriꢀs
conditions” (120 mm ethylene). The origins of the marked
activity of allyl bromide, and its low propensity for RC-CM,
are not at all clear and warrant detailed further investiga-
tion.
[10] An h3-coordination mode in vinylalkylidene complexes has been re-
ported to attenuate the rate of metathesis, see: T. M. Trnka, M. W.
Day, R. H. Grubbs, Organometallics 2001, 20, 3845–3847; cycle B
allows more efficient catalytic turnover by attenuating side reac-
tions, such as reaction with the alkyne moiety of the substrate,
which can be detected by ESI-MS (G. C. Lloyd-Jones, A. J. Robin-
son, unpublished results); for reactions involving terminal-alkyne-
Experimental Section
Ring-closing enyne methathesis of 1a in the presence of 100 mol%
[1,1-2H2]-decene (Figure 1b and Scheme 4): A solution of 1a (50 mg,
0.24 mmol, 0.06m overall), dodecane (internal standard), [2H]2-decene
(33 mg, 0.24 mmol, 0.06m overall, 100 mol%) and [2H7]-2a (10 mg,
0.048 mmol, 20 mol%) in dry CH2Cl2 (2 cm3) was stirred at room temper-
ature under nitrogen. A solution of 3a (9.8 mg, 0.003m overall, 5 mol%)
in dry CH2Cl2 (2 cm3) was then added by means of a gas-tight syringe.
The reaction was sampled periodically, removing two 2ꢂ50 mL samples,
which were quenched into an excess of PPh3 in CH2Cl2 (1 cm3) and the
solution then passed through a plug of silica-gel. For each pair of sam-
ples, the first was directly analysed for conversion by GC (on a Hewlett
Packard HP5890 with flame ionisation detector; split ratio 1:50; helium
at 1 cm3 minꢀ1; Alltech ECꢃ, 30 m ꢂ 0.25 mm ID, 0.25 mm film thick-
ness.) and by MS (Varian Saturn 2200 GC/MS) for the [2H2]-methylidene
distribution in 1a (m/z: 210 and 212); 2a (m/z: 210 and 212); and [2H7]-
2a (m/z: 217 and 219). Bromine was added dropwise to the second
sample until a deep red colour persisted, and this was then discharged
with excess pentene. The colourless solution was analysed by MS for the
[2H2]-methylidene distribution in the decene (analysis of deca-1,3-dienyl
cation [C10H17]+ daughter ion; m/z: 137 and 139).
type enyne substrates, Grubbs I catalyst
than Grubbs II catalyst.
ACHTUNGERTN(NUNG 3a) is much more efficient
[11] The benzylidene pre-catalyst (3a) connects with the cycle through
alkene–alkylidene exchange (6!4) liberating styrene, R=Ph. The
methylidene complex [RuCl2ACHTNUGTRENN(UG PCy3)2ACHTUNGTREN(NUNG =CH2)], which undergoes slow
PCy3 dissociation is a very poor catalyst for RCM of 1a, with or
without an atmosphere of ethylene, and with or without styrene and
ethylene.
[12] The second alkene–alkylidene exchange step involving intermediate
6 must also proceed by orientation “a”, as orientation “b” will result
in cross-metathesis to generate the alkene homologated enyne.
Analogously, reaction of 6 with product 2 in orientation “b” will
result in RC-CM product 7, as would reaction of 6 with the alkyne
terminus of 1.
[13] See, for example: a) H.-Y. Lee, H. Y. Kim, H. Tae, B. G. Kim, J.
Lee, Org. Lett. 2003, 5, 3439–3442; b) F. Royer, C. Vilain, L.
Elkaꢅm, L. Grimaud, Org. Lett. 2003, 5, 2007–2009; c) T. Kitamura,
Y. Sato, M. Mori, Tetrahedron 2004, 60, 9649–9657; d) D. A.
Kummer, J. B. Brenneman, S. F. Martin, Tetrahedron 2006, 62,
11437–11449.
[14] This suggests that up to xꢁ10, the magnitude of kSAT is determined
by the impact of the length of “R” on the rate of alkene-alkylidene
exchange of 1 with 6; above x=10, the extension in chain length is
not sufficiently proximal to the ligands on the ruthenium centre.
[15] The kobs values varied from batch to batch of catalyst 3a and thus
data sets for establishing kobs versus [CxH2x] and kSAT/k0 were con-
ducted with a single batch of catalyst.
Acknowledgements
We thank DSM for generous funding of this work. G.C.L.J. is a Royal So-
ciety Wolfson Research Merit Award holder.
[16] Under these conditions, less than 4% RC-CM and decene homo-
CM (!octadecene) occurs. The maximum ethylene concentration
that would be generated is 4.8 mm, leading to about 5% rate en-
hancement if ethylene saturation kinetics proceed from 0.1m.
[17] Analysis under saturation conditions ([n-alk-1-ene]=0.3m) at
Keywords: enynes · isotopic labeling · metathesis · reaction
mechanisms · ruthenium
60 min yielded ([7a]/ACTHNUTRGNEUNG
[2a+7a])60 (%)=1.5x+1.7, R2 =0.96].
[18] a) T. Imahori, H. Ojima, H. Tateyama, Y. Mihara, H. Takahata, Tet-
rahedron Lett. 2008, 49, 265–267; b) T. Imahori, H. Ojima, Y. Yoshi-
mura, H. Takahata, Chem. Eur. J. 2008, 14, 10762–10771.
[19] Cy3P dissociation is required to engender catalytic turnover, and
capture of this by allyl bromide was probed as a possible source of
the marked acceleration as compared to the other allyl species.
However, 1) 5 mol% [Cy3P–allyl]Br was inert as an additive and
2) the rate of RCM of diallyl dimethylmalonate was unaffected by
5 mol% allyl bromide, whereas propargyl allyl dimethylmalonate
(1a) underwent 17-fold enhancement.
[20] Reaction of 3a with allyl bromide only resulted in extensive decom-
position due to allylation of dissociated Cy3P; in contrast, the analo-
gous reaction with allyl chloride[21] (three cycles of exchange) afford-
ed 3b, contaminated with approximately 15% 3a.
[21] P. Schwab R. B. Grubbs, J. W. Ziller, J. Am. Chem. Soc. 1996, 118,
100–110.
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[4] Between 1998–2010, there were over 182 examples citing use of
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Received: May 31, 2010
Published online: July 21, 2010
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Chem. Eur. J. 2010, 16, 9449 – 9452